DNA damage can contribute to tumorigenesis, but is also used to treat cancer. As a treatment, the induction of DNA damage aims to limit the viability of cancer cells. In order to improve treatments, it is important to understand the underlying mechanisms that cause DNA damage induced toxicity to a cell. As such, our work on the DNA damage response aims to identify and characterize determinants of DNA damage sensitivity. We strive to answer questions such as: are there differences in cellular sensitivity to a single double strand break, and if so, what causes such differential DNA damage sensitivity? What is the interplay between physiological processes and DNA damage repair and sensitivity? What factors contribute to the differences in DNA damage sensitivity in normoxic and hypoxic conditions? Can we identify novel factors that contribute to limiting the toxicity of DNA damage? Answering these important questions may help to better understand the response of a tumor to DNA damaging agents that are commonly used to treat cancer.
In recent work, we have identified several determinants of DNA damage induced toxicity. We showed that DNA damage induced cell cycle checkpoints are wired differentially during the cell cycle (REF Indra en review indra), and that the cell cycle phase when DNA damage occurs influences toxicity (refs Krenning mol cell, Feringa, Nat Comms ’16). Sparked by our observation that DNA damage toxicity is not necessarily dependent on the amount of DNA damage (REF Feringa, Nat Comms ’18), we have now started investigating the effect of location on the toxicity of DNA damage.